The metabolic and growth-stimulatory effects of insulin are mediated by the insulin receptor, an a2[unreadable]2 transmembrane glycoprotein with intrinsic protein tyrosine kinase activity. Insulin binding to the extracellular domains of the receptor induces a structural rearrangement that facilitates autophosphorylation of specific tyrosine residues in the cytoplasmic domains. Tyrosine phosphorylation serves to stimulate the catalytic activity of the kinase domain of the receptor and to create recruitment sites for downstream signaling proteins. The overall goal of this proposal is to understand the structural/molecular mechanisms governing recruitment to the insulin receptor of positive and negative regulators of insulin signaling. The Specific Aims of this proposal are: 1. Molecular mechanisms governing downregulation of the insulin receptor by Grb14 2. Molecular mechanisms underlying downregulation of the insulin receptor by PTP1B 3. Molecular mechanisms governing IRS2 recruitment to and phosphorylation by the insulin receptor The main experimental techniques to be used are x-ray crystallography, in vitro binding measurements, and cell-based functional assays. The results obtained from this proposal should contribute significantly to our understanding of the molecular mechanisms by which insulin signaling is propagated and attenuated. Relevance: The prevalence of non-insulin-dependent (type II) diabetes is increasing at an alarming rate in developed countries. By understanding at the molecular level how the insulin receptor is regulated, we hope to facilitate efforts to design small-molecule agonists and inhibitors that could potentially be used as anti-diabetic therapeutics.